The developing central nervous system is particularly vulnerable to environmental toxicants such as heavy metals. While lead (Pb) poisoning has been extensively studied, the neurotoxicities and dose-effect relationships associated with other heavy metals, such as arsenic (As) and manganese (Mn), are poorly understood. Data are even more limited on the effects of joint exposures to these metals, even though this exposure scenario more accurately reflects the real world situation. In this project we will build upon an ongoing birth cohort study of 750 mothers and their children at a former hard rock mining community, the Tar Creek, OK, Superfund mega-site. To date, children have been followed to age 2 years, involving the collection of extensive Pb, Mn, and As biomarker data (blood, hair, nails), providing a record of lifetime (including prenatal) exposures to these metals. In the proposed project, assessments will be conducted when children are 5.5 years of age. At that time, Mn and Pb will be measured in blood; Mn, As, and selenium (Se) in hair; and As and Se in nails. The neurodevelopmental assessment will include tests of intelligence, memory, visual- motor/spatial abilities, executive functions, and behavior. Data analyses will model the associations between neurodevelopment and individual metals and between neurodevelopment and joint exposures to metals. Another goal is to determine if genetic susceptibility factors modify the associations between metal exposures and neurodevelopment, focusing on genetic variations in 4 pathways chosen to reflect metal metabolism or synaptic plasticity: iron metabolism (HFE, transferrin, DMT-1), cholesterol metabolism (apolipoprotein E), neurotransmitter metabolism (dopamine transporter, dopamine D4 receptor, norepinephrine transporter, monoamine oxidase, catechol O-methyltransferase, NMDA receptor, 5-HT1A receptor), and methylation metabolism (methylenetetrahydrofolate reductase, GST- M1, T1, P1, omega, purine nucleoside phosphorylase, cytosolic serine hydroxymethyltransferase). This prospective study will provide the most comprehensive data to date on the potential neurodevelopmental correlates of Mn and As exposures, and on the potential interactions among Pb, Mn, and As exposures. This prospective study of children from birth will provide the most comprehensive data available on the potential adverse effects on neurodevelopment of exposure to the heavy metals arsenic and manganese. The effects of exposures to combinations of metals, including lead, is also a major focus. This more closely mirrors real world exposures, which invariably involve a mixture of compounds rather than a single compound.